The invention relates to cocaine analogues.
The abuse of cocaine is a health problem of national significance. Despite intensive study, there is still inadequate information about the neurochemical mechanisms mediating cocaine's detrimental effects and abuse liability or about drug therapies for cocaine abuse.
Recent studies have identified biologically relevant binding sites for cocaine in brain tissue of rodents (Reith et al., Biochem. Pharmacol. 35:1123-1129, 1986; Kennedy and Hanbauer, 41:172-178, 1983; Calligaro and Eldefrawi, J. Pharmacol. Exp. Ther. 243:61-68, 1987; Calligaro and Eldefrawi, Membrane Biochem. 7:87-106, 1988), humans (Schoemaker et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 329:227-235, 1985), and nonhuman primates (Madras et al., FASEB J. 2:A1137, 1988; Madras et al., ASP/ASPET Abstr. A197, 1988; Madras et al., J. Pharmacol. Exp. Ther. 251:131-141, 1989). These sites, which are associated with monoamine uptake systems, can be labeled with [.sup.3 H]cocaine and have properties characteristic of a pharmacological receptor. First, the sites bind [.sup.3 H]cocaine saturably with affinities in the 10.sup.-8 to 10.sup.-6 M range, concentrations comparable to those achieved in brain or plasma after peripheral administration of cocaine to animals or humans (Van Dyke et al., Science 191.:859-861, 1976; Misra et al., Drug Alcohol Depend. Z:261-272, 1977; Javaid et al., Science 200:227-228, 1978). Second, the sites display stereoselectivity for (-)-cocaine over (+)-cocaine or its C-2 epimer pseudococaine (Madras et al., APS/ASPET Abstr. A197, 1988; Madras et al., J. Pharmacol. Exp. Ther. 251:131-141, 1989). Third, and perhaps most importantly, there is a high degree of correspondence between the relative potencies of various cocaine analogs for producing cocaine-like effects in vivo and relative binding affinities of the drugs for [.sup.3 H]cocaine binding sites in vitro. Specifically, the ED50 values of cocaine and several cocaine analogs for producing behavioral stimulation (Spealman et al., J. Pharmacol. Exp. Ther. 251:142-149, 1989) or for maintaining self-administration in non-human primates (Bergman et al., J. Pharmacol. Exp. Ther. 251:150-155, 1989) parallel their IC.sub.50 values for displacing [.sup.3 H]cocaine from binding sites in monkey brain (Madras et al., FASEB J. Z:A1137, 1988; Madras et al., J. Pharmacol. Exp. Ther. 251:131-141, 1989).
Although cocaine inhibits the uptake of dopamine, serotonin, and norepinephrine with similar potencies, [.sup.3 H]cocaine recognition sites on the dopamine transporter are particularly relevant to the behavioral effects of cocaine (Reith et al., Biochem. Pharmacol. 35:1123-1129, 1986; Madras et al., FASEB J. Z:A1137, 1988; Madras et al., J. Pharmacol. Exp. Ther. 251:131-141, 1989, Bergman et al., J. Pharmacol. Exp. Ther. 251:150-155, 1989; Spealman et al., J. Pharmacol. Exp. Ther. 251:142-149, 1989). Cocaine congeners and other drugs block behaviorally relevant [.sup.3 H]cocaine binding in monkey caudate-putamen with a rank order of potency that corresponds closely to their reported potencies for inhibiting uptake of dopamine but not norepinephrine or serotonin (Madras et al., J. Pharmacol. Exp. Ther. 251:131-141, 1989). Furthermore, selective norepinephrine or serotonin inhibitors do not produce the characteristic stimulant, reinforcing and interoceptive effects elicited by cocaine (Spealman et al., J. Pharmacol. Exp. Ther. 251:142-149, 1989; Spealman et al., J. Pharmacol. Exp. Ther. 258:945-953, 1991; Bergman et al., J. Pharmacol. Exp. Ther. 251:150-155, 1989). Together, these studies support the view that cocaine recognition sites associated with the dopamine transporter are important mediators of the behavioral effects of cocaine.
Further clarification of the mechanisms by which cocaine and related drugs alter behavior and maintain abuse will likely emerge from molecular characterization of cocaine receptor sites and imaging these sites in the brain. These studies have been hampered, however, by the relative inefficiency of [.sup.3 H]cocaine as a radioligand and the lack of versatile probes to elucidate the molecular properties of the receptor complex. In particular, [.sup.3 H]cocaine binds to the receptor with modest affinity in all brain regions studied (K.sub.0.50 .apprxeq.300 nM) and dissociates rapidly. This modest affinity of [.sup.3 H]cocaine (25-30 Ci/mmole) make it a relatively poor tag for imaging cocaine receptors, either in vitro or in vivo.
Drug therapies for cocaine abuse also are needed, and therapeutic agents based on cocaine congeners are proposed.
There is also a need for suitable agents and procedures to diagnose neurodegenerative disorders, such as Parkinson's disease. In particular, exclusion of Parkinson's disease as the cause of symptoms at an early stage may be useful information in diagnosing other conditions such as Alzheimer's disease. In addition, early diagnosis of Parkinson's disease facilitates the introduction of prophylactic drug therapy (e.g., deprenyl administration) prior to the onset of symptoms. There is also a need for compounds to neurodegenerative disorders characterized by Parkinson's disease.